B cell translocation gene 2 expression levels in human granulosa cells is negatively associated with in vitro fertilization/intracytoplasmic sperm injection outcomes: a pilot study.

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Abstract

Purpose This study aimed to monitor the expression of B-cell translocation gene 2 (BTG2) in granulosa cells of patients undergoing IVF/ICSI with respect blastocyst quality outcomes.

Methods

We recruited 181 women undergoing IVF/ICSI cycles for infertility. Granulosa cells were extracted from follicular fluid. BTG2 expression level of granulosa cells were stratified into tertiles (low, middle, and high), and the patients of each tertile were compared for outcome indicators by Kruskal–Wallis analysis. Spearman’s correlation analyses were used to evaluate the correlation between BTG2 mRNA levels and outcome indicators. Generalized linear models and generalized additive models with smoothing splines were used to adjust for potential confounders.

Results

Patients in the low BTG2 tertile had higher oocyte retrieval, fertilization, blastocyst formation, and high-quality blastocyst rates than those in the high BTG2 tertile. Patients in the high BTG2 tertile exhibited a downward trend in implantation and clinical pregnancy rates compared to those in the low or middle BTG2 tertiles, whereas the early pregnancy loss rate showed an upward trend, although the difference was not significant. After adjusting for confounding factors, the expression level of BTG2 was negatively correlated with oocyte retrieval, blastocyst formation, and high-quality blastocyst rates. Stratified analysis of AMH > 4 ng/ml showed elevated BTG2 expression was associated with reduced oocyte retrieval, fertilization, cleavage, blastocyst formation, and high-quality blastocyst rates. No differences in these outcomes were observed in patients with AMH ≤ 4 ng/ml.

Conclusion

In women with high AMH levels (> 4 ng/ml) elevated BTG2 expression in granulosa cells was associated with poor quality blastocyst outcomes. Similar content being viewed by others Data availability The data analyzed during the current study is not publicly available due to confidence reasons, but can be obtained from the corresponding author upon reasonable request.

References

Rizos D, Ward F, Duffy P, et al. Consequences of bovine oocyte maturation, fertilization or early embryo development in vitro versus in vivo: implications for blastocyst yield and blastocyst quality[J]. Mol Reprod Dev. 2002;61(2):234–48. https://doi.org/10.1002/mrd.1153. Rienzi L, Vajta G, Ubaldi F. Predictive value of oocyte morphology in human IVF: a systematic review of the literature[J]. Hum Reprod Update. 2011;17(1):34–45. https://doi.org/10.1093/humupd/dmq029. Wang CM, Liu CM, Jia XZ, et al. Expression of mitochondrial transcription factor A in granulosa cells: implications for oocyte maturation and in vitro fertilization outcomes[J]. J Assist Reprod Genet. 2024;41(2):363–70. https://doi.org/10.1007/s10815-023-03001-9. Bromer JG, Seli E. Assessment of embryo viability in assisted reproductive technology: shortcomings of current approaches and the emerging role of metabolomics[J]. Curr Opin Obstet Gynecol. 2008;20(3):234–41. https://doi.org/10.1097/GCO.0b013e3282fe723d. Fragouli E, Lalioti MD, Wells D. The transcriptome of follicular cells: biological insights and clinical implications for the treatment of infertility[J]. Hum Reprod Update. 2014;20(1):1–11. https://doi.org/10.1093/humupd/dmt044. Luddi A, Gori M, Marrocco C, et al. Matrix metalloproteinases and their inhibitors in human cumulus and granulosa cells as biomarkers for oocyte quality estimation[J]. Fertil Steril. 2018;109(5):930–9. https://doi.org/10.1016/j.fertnstert.2018.01.030. Iager AE, Kocabas AM, Otu HH, et al. Identification of a novel gene set in human cumulus cells predictive of an oocyte’s pregnancy potential[J]. Fertil Steril. 2013;99(3):745–52. https://doi.org/10.1016/j.fertnstert.2012.10.041. Jiang JY, Xiong H, Cao M, et al. Mural granulosa cell gene expression associated with oocyte developmental competence[J]. J Ovarian Res. 2010;3:6. https://doi.org/10.1186/1757-2215-3-6. Uyar A, Torrealday S, Seli E. Cumulus and granulosa cell markers of oocyte and embryo quality[J]. Fertil Steril. 2013;99(4):979–97. https://doi.org/10.1016/j.fertnstert.2013.01.129. Qi F, Liu W, Tan B, et al. BTG2 suppresses renal cell carcinoma progression through N6-methyladenosine[J]. Front Oncol. 2022;12:1049928. https://doi.org/10.3389/fonc.2022.1049928. Mao B, Zhang Z, Wang G. BTG2: a rising star of tumor suppressors (review)[J]. Int J Oncol. 2015;46(2):459–64. https://doi.org/10.3892/ijo.2014.2765. Yuniati L, Scheijen B, van der Meer LT, et al. Tumor suppressors BTG1 and BTG2: Beyond growth control[J]. J Cell Physiol. 2019;234(5):5379–89. https://doi.org/10.1002/jcp.27407. Kawakubo H, Brachtel E, Hayashida T, et al. Loss of B-cell translocation gene-2 in estrogen receptor-positive breast carcinoma is associated with tumor grade and overexpression of cyclin d1 protein[J]. Cancer Res. 2006;66(14):7075–82. https://doi.org/10.1158/0008-5472.CAN-06-0379. Li F, Liu J, Park ES, et al. The B cell translocation gene (BTG) family in the rat ovary: hormonal induction, regulation, and impact on cell cycle kinetics[J]. Endocrinology. 2009;150(8):3894–902. https://doi.org/10.1210/en.2008-1650. Rouault JP, Falette N, Guehenneux F, et al. Identification of BTG2, an antiproliferative p53-dependent component of the DNA damage cellular response pathway[J]. Nat Genet. 1996;14(4):482–6. https://doi.org/10.1038/ng1296-482. Kim SH, Jung IR, Hwang SS. Emerging role of anti-proliferative protein BTG1 and BTG2[J]. BMB Rep. 2022;55(8):380–8. https://doi.org/10.5483/BMBRep.2022.55.8.092. Chermula B, Brazert M, Jeseta M, et al. Transcriptomic pattern of genes regulating protein response and status of mitochondrial activity are related to oocyte maturational competence-A transcriptomic study[J]. Int J Mol Sci. 2019;20(9):2238. https://doi.org/10.3390/ijms20092238. Ozegowska K, Dyszkiewicz-Konwinska M, Celichowski P, et al. Expression pattern of new genes regulating female sex differentiation and in vitro maturational status of oocytes in pigs[J]. Theriogenology. 2018;121:122–33. https://doi.org/10.1016/j.theriogenology.2018.08.019. Park JI, Kim SG, Baek MW, et al. B-cell translocation gene 2: expression in the rat ovary and potential association with adenine nucleotide translocase 2 in mitochondria[J]. Mol Cell Endocrinol. 2013;367(1–2):31–40. https://doi.org/10.1016/j.mce.2012.12.013. Schmidt J, de Avila J, McLean D. Regulation of protein tyrosine phosphatase 4a1, B-cell translocation gene 2, nuclear receptor subfamily 4a1 and diacylglycerol O-acyltransferase 1 by follicle stimulating hormone in the rat ovary[J]. Reprod Fertil Dev. 2006;18(7):757–65. https://doi.org/10.1071/rd05167. Rao M, Zeng Z, Zhang Q, et al. Thyroid autoimmunity is not associated with embryo quality or pregnancy outcomes in euthyroid women undergoing assisted reproductive technology in China[J]. Thyroid. 2023;33(3):380–8. https://doi.org/10.1089/thy.2022.0184. Rao M, Wang H, Zhao S, et al. Subclinical hypothyroidism is associated with lower ovarian reserve in women aged 35 years or older[J]. Thyroid. 2020;30(1):95–105. https://doi.org/10.1089/thy.2019.0031. Rao M, Yang Z, Su C, et al. Paternal subclinical hypothyroidism affects the clinical outcomes of in vitro fertilization/intracytoplasmic sperm injection[J]. Thyroid. 2021;31(1):12–22. https://doi.org/10.1089/thy.2020.0154. Guerif F, Le Gouge A, Giraudeau B, et al. Limited value of morphological assessment at days 1 and 2 to predict blastocyst development potential: a prospective study based on 4042 embryos[J]. Hum Reprod. 2007;22(7):1973–81. https://doi.org/10.1093/humrep/dem100. Chen C, Kattera S. Comparison of pronuclear zygote morphology and early cleavage status of zygotes as additional criteria in the selection of day 3 embryos: a randomized study[J]. Fertil Steril. 2006;85(2):347–52. https://doi.org/10.1016/j.fertnstert.2005.07.1319. Li J, Du M, Zhang Z, et al. Does a poor-quality embryo have an adverse impact on a good-quality embryo when transferred together?[J]. J Ovarian Res. 2018;11(1):78. https://doi.org/10.1186/s13048-018-0452-6. Gardner DK, Schoolcraft WB. Culture and transfer of human blastocysts[J]. Curr Opin Obstet Gynecol. 1999;11(3):307–11. https://doi.org/10.1097/00001703-199906000-00013. Ghobara T, Gelbaya TA, Ayeleke RO. Cycle regimens for frozen-thawed embryo transfer[J]. Cochrane Database Syst Rev. 2017;7(7):D3414. https://doi.org/10.1002/14651858.CD003414.pub3. Rao M, Wang L, Yan G, et al. Normal-range paternal serum-free thyroxine concentrations and outcomes of assisted reproductive technologies[J]. Thyroid. 2022;32(6):705–13. https://doi.org/10.1089/thy.2022.0049. Nassan FL, Arvizu M, Minguez-Alarcon L, et al. Marijuana smoking and outcomes of infertility treatment with assisted reproductive technologies[J]. Hum Reprod. 2019;34(9):1818–29. https://doi.org/10.1093/humrep/dez098. Rosen EM, Minguez-Alarcon L, Meeker JD, et al. Urinary oxidative stress biomarker levels and reproductive outcomes among couples undergoing fertility treatments[J]. Hum Reprod. 2019;34(12):2399–409. https://doi.org/10.1093/humrep/dez228. Jiang Z, Shi C, Han H, et al. Mitochondria-related changes and metabolic dysfunction in low prognosis patients under the POSEIDON classification[J]. Hum Reprod. 2021;36(11):2904–15. https://doi.org/10.1093/humrep/deab203. Liu K, Mao X, Pan F, et al. Correlation analysis of sperm DNA fragmentation index with semen parameters and the effect of sperm DFI on outcomes of ART[J]. Sci Rep. 2023;13(1):2717. https://doi.org/10.1038/s41598-023-28765-z. Racca A, De Munck N, Santos-Ribeiro S, et al. Do we need to measure progesterone in oocyte donation cycles? A retrospective analysis evaluating cumulative live birth rates and embryo quality[J]. Hum Reprod. 2020;35(1):167–74. https://doi.org/10.1093/humrep/dez238. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method[J]. Methods. 2001;25(4):402–8. https://doi.org/10.1006/meth.2001.1262. Hou Y, Wang L, Li Y, et al. Serum levels of anti-Mullerian hormone influence pregnancy outcomes associated with gonadotropin-releasing hormone antagonist treatment: a retrospective cohort study[J]. Sci Rep. 2023;13(1):2127. https://doi.org/10.1038/s41598-023-28724-8. Kaltsas A, Moustakli E, Zikopoulos A, et al. Impact of advanced paternal age on fertility and risks of genetic disorders in offspring[J]. Genes (Basel). 2023;14(2):486. https://doi.org/10.3390/genes14020486. Sartorius GA, Nieschlag E. Paternal age and reproduction[J]. Hum Reprod Update. 2010;16(1):65–79. https://doi.org/10.1093/humupd/dmp027. Sharma R, Agarwal A, Rohra VK, et al. Effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring[J]. Reprod Biol Endocrinol. 2015;13:35. https://doi.org/10.1186/s12958-015-0028-x. Harris BS, Jukic AM, Truong T, et al. Markers of ovarian reserve as predictors of future fertility[J]. Fertil Steril. 2023;119(1):99–106. https://doi.org/10.1016/j.fertnstert.2022.10.014. Prieto-Huecas L, Piera-Jordan CA, Serrano DLCV, et al. Assessment of nutritional status and its influence on ovarian reserve: a systematic review[J]. Nutrients. 2023;15(10):2280. https://doi.org/10.3390/nu15102280. Cedars MI. Evaluation of female fertility-AMH and ovarian reserve testing[J]. J Clin Endocrinol Metab. 2022;107(6):1510–9. https://doi.org/10.1210/clinem/dgac039. Testing and interpreting measures of ovarian reserve. a committee opinion[J]. Fertil Steril. 2020;114(6):1151–7. https://doi.org/10.1016/j.fertnstert.2020.09.134. Pathare A, Loid M, Saare M, et al. Endometrial receptivity in women of advanced age: an underrated factor in infertility[J]. Hum Reprod Update. 2023;29(6):773–93. https://doi.org/10.1093/humupd/dmad019. Van Sinderen M, Menkhorst E, Winship A, et al. Preimplantation human blastocyst-endometrial interactions: the role of inflammatory mediators[J]. Am J Reprod Immunol. 2013;69(5):427–40. https://doi.org/10.1111/aji.12038. Kidd SA, Eskenazi B, Wyrobek AJ. Effects of male age on semen quality and fertility: a review of the literature[J]. Fertil Steril. 2001;75(2):237–48. https://doi.org/10.1016/s0015-0282(00)01679-4. Evenson DP, Djira G, Kasperson K, et al. Relationships between the age of 25,445 men attending infertility clinics and sperm chromatin structure assay (SCSA(R)) defined sperm DNA and chromatin integrity[J]. Fertil Steril. 2020;114(2):311–20. https://doi.org/10.1016/j.fertnstert.2020.03.028. Vaughan DA, Tirado E, Garcia D, et al. DNA fragmentation of sperm: a radical examination of the contribution of oxidative stress and age in 16 945 semen samples[J]. Hum Reprod. 2020;35(10):2188–96. https://doi.org/10.1093/humrep/deaa159. Nguyen-Powanda P, Robaire B. Oxidative stress and reproductive function in the aging male[J]. Biology (Basel). 2020;9(9):282. https://doi.org/10.3390/biology9090282. Nikitaras V, Zander-Fox D, McPherson NO. Improving sperm oxidative stress and embryo quality in advanced paternal age using idebenone in vitro-a proof-of-concept study[J]. Antioxidants (Basel). 2021;10(7):1079. https://doi.org/10.3390/antiox10071079. Xi W, Gong F, Lu G. Correlation of serum anti-Mullerian hormone concentrations on day 3 of the in vitro fertilization stimulation cycle with assisted reproduction outcome in polycystic ovary syndrome patients[J]. J Assist Reprod Genet. 2012;29(5):397–402. https://doi.org/10.1007/s10815-012-9726-x. Tal R, Seifer CM, Khanimov M, et al. High serum antimullerian hormone levels are associated with lower live birth rates in women with polycystic ovarian syndrome undergoing assisted reproductive technology[J]. Reprod Biol Endocrinol. 2020;18(1):20. https://doi.org/10.1186/s12958-020-00581-4. Jonard S, Dewailly D. The follicular excess in polycystic ovaries, due to intra-ovarian hyperandrogenism, may be the main culprit for the follicular arrest[J]. Hum Reprod Update. 2004;10(2):107–17. https://doi.org/10.1093/humupd/dmh010. Chen X, Cao M, Yuan C, et al. Follicular fluid exosomes inhibit expression of BTG2 and promote glucose uptake in granulosa cells by delivering miR-21-5p[J]. Theriogenology. 2024;218:45–55. https://doi.org/10.1016/j.theriogenology.2024.01.029. Maucieri AM, Townson DH. Evaluating the impact of the hexosamine biosynthesis pathway and O-GlcNAcylation on glucose metabolism in bovine granulosa cells[J]. Mol Cell Endocrinol. 2023;564:111863. https://doi.org/10.1016/j.mce.2023.111863. Su Q, Xu ZX, Xiong ML, et al. The oncogenic miR-27a/BTG2 axis promotes obesity-associated hepatocellular carcinoma by mediating mitochondrial dysfunction[J]. Neoplasma. 2022;69(4):820–31. https://doi.org/10.4149/neo_2022_211227N1837. Rodriguez-Varela C, Labarta E. Role of mitochondria transfer in infertility: a commentary[J]. Cells. 2022;11(12):1867. https://doi.org/10.3390/cells11121867. Kirillova A, Smitz J, Sukhikh GT, et al. The role of mitochondria in oocyte maturation[J]. Cells. 2021;10(9):2484. https://doi.org/10.3390/cells10092484. Belli M, Palmerini MG, Bianchi S, et al. Ultrastructure of mitochondria of human oocytes in different clinical conditions during assisted reproduction[J]. Arch Biochem Biophys. 2021;703:108854. https://doi.org/10.1016/j.abb.2021.108854. Trebichalska Z, Kyjovska D, Kloudova S, et al. Cytoplasmic maturation in human oocytes: an ultrastructural study dagger[J]. Biol Reprod. 2021;104(1):106–16. https://doi.org/10.1093/biolre/ioaa174. Dumollard R, Campbell K, Halet G, et al. Regulation of cytosolic and mitochondrial ATP levels in mouse eggs and zygotes[J]. Dev Biol. 2008;316(2):431–40. https://doi.org/10.1016/j.ydbio.2008.02.004. Shang D, Xie C, Hu J, et al. Pancreatic cancer cell-derived exosomal microRNA-27a promotes angiogenesis of human microvascular endothelial cells in pancreatic cancer via BTG2[J]. J Cell Mol Med. 2020;24(1):588–604. https://doi.org/10.1111/jcmm.14766. Tirone F. The gene PC3(TIS21/BTG2), prototype member of the PC3/BTG/TOB family: regulator in control of cell growth, differentiation, and DNA repair?[J]. J Cell Physiol. 2001;187(2):155–65. https://doi.org/10.1002/jcp.1062. Lin D, Ran J, Zhu S, et al. Effect of GOLPH3 on cumulus granulosa cell apoptosis and ICSI pregnancy outcomes[J]. Sci Rep. 2017;7(1):7863. https://doi.org/10.1038/s41598-017-08343-w. Jancar N, Kopitar AN, Ihan A, et al. Effect of apoptosis and reactive oxygen species production in human granulosa cells on oocyte fertilization and blastocyst development[J]. J Assist Reprod Genet. 2007;24(2–3):91–7. https://doi.org/10.1007/s10815-006-9103-8.

Acknowledgements

We would like to thank the Editage (www.editage.cn) for English language editing. Funding This research was funded by the National Natural Science Foundation of China (grant number 82160281), Science and Technology Plan Project of Yunnan Provincial Department of Science and Technology (grant number 202401AY070001-032), Yunnan Support Program of High Level Talents Cultivation Famous Medical Project (grant number RLMY20200017), and Dali Science and Technology Planning Project (grant number 2021085). Author information Authors and Affiliations Contributions Conceptualization, J.H. and L.T.; methodology, H.W. and L.Z.; software, J.H. and L.Z.; validation, L.W., J.Y., and M.S.; formal analysis, Y.C.; resources, H.W.; data curation, M.R.; writing—original draft preparation, J.H.; writing—review and editing, M.R., S.Z., and L.T; visualization, J.H., L.W., J.Y., Y.C., and M.S; supervision, S.Z.; project administration, M.R. and L.T.; funding acquisition, L.T. All authors have read and agreed to the published version of the manuscript. All authors read and approved the final manuscript. Corresponding authors Ethics declarations Ethical approval The study was conducted in accordance with the Declaration of Helsinki, and approved by the hospital Ethics Committee of the First Affiliated Hospital of Kunming Medical University (protocol code: No. (2023) Ethical Review No. 163 and date of approval: 2-Nov-2023). Competing interests The authors declare no competing interests. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Information Below is the link to the electronic supplementary material. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Luo, J., Wang, H., Zhou, L. et al. B cell translocation gene 2 expression levels in human granulosa cells is negatively associated with in vitro fertilization/intracytoplasmic sperm injection outcomes: a pilot study. J Assist Reprod Genet 42, 909–922 (2025). https://doi.org/10.1007/s10815-025-03391-y Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s10815-025-03391-y

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